As gut transplantation becomes clinical reality, our understanding of enteric function of the transplanted gut lags far behind. Most previous experimental work has addressed the immunobiology this proposal, in contrast, addresses the enteric physiology of the transplanted gut, a new and important field with direct physiologic import and potential clinical application. This competitive renewal extends the LONG TERM OBJECTIVE of our research program to elucidate neurohormonal mechanisms controlling motility and absorption via study of the denervated (transplanted) gut. This proposal purposely uses selected models of canine autotransplantation and rat isografting to dissect out the effects of denervation physiology specifically devoid of any confounding effects of immune phenomena and immunosuppression on enteric function. Our thesis is that before we can understand and manipulate function of the transplanted gut, we must first understand normal function of the denervated gut.
SPECIFIC AIMS : Part A - Motility: To elucidate the neurohormonal mechanisms controlling A1) coordinated motor activity of the stomach and small intestine and A2) global and specific local patterns of ileal motility; and to determine A3) alterations in smooth muscle contractility, electrophysiologic mechanisms modulating smooth muscle cell contractility, and mechanisms of adaptation of enteric smooth muscle to chronic denervation (transplantation). Part B - Absorption: B1) To characterize absorption of water and electrolytes, carrier-mediated nutrients (specific amino acids, sugars), and substances with site-specific uptake mechanisms (bile acids) after gut transplantation. B2) To focus on mechanisms controlling absorptive function and temporal adaptation to transplantation by studying responses to postprandial proabsorptive/prosecretory stimuli, kinetics of brush border carrier-mediated uptake of amino acids and glucose, specific brush border enzyme activity, tissue morphometry, and concentration of regulatory peptides within specific regions of the gut wall. METHODOLOGY involves in vivo techniques to address integrative mechanisms of control in the whole animal and in vitro techniques to study local specific mechanistic questions. Motor function is evaluated in vivo by myoelectric activity and intraluminal manometry and complimented by specific in vitro measures of smooth muscle contractility and membrane potential using intracellular electrophysiologic techniques. Absorptive function is evaluated in vivo by intestinal perfusion techniques and complicated by in vitro techniques to evaluate kinetics of vesicle transport of amino acids and glucose, quantitative assay of tissue enzyme activities, immunohistochemistry and immunoassay of tissue regulatory peptides, and light and scanning electron microscopy. This proposal will define new and important neural and hormonal mechanisms regulating motor and absorptive function of the gut. Application of these observations are pertinent to selected aspects of clinical gut transplantation in man.
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